Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells
Glioblastoma (GBM) is a highly aggressive brain tumor and almost all patients die because of relapses. GBM-derived cells undergo cell death without nuclear fragmentation upon treatment with different apoptotic agents. Nuclear dismantling determines the point-of-no-return in the apoptotic process. DF...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/21/5579 |
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| author | Laura Martínez-Escardó Montse Alemany María Sánchez-Osuna Alejandro Sánchez-Chardi Meritxell Roig-Martínez Salvio Suárez-García Daniel Ruiz-Molina Noemi Vidal Gerard Plans Carles Majós Judit Ribas María Antonia Baltrons Jose R. Bayascas Carlos Barcia Jordi Bruna Victor J. Yuste |
| author_facet | Laura Martínez-Escardó Montse Alemany María Sánchez-Osuna Alejandro Sánchez-Chardi Meritxell Roig-Martínez Salvio Suárez-García Daniel Ruiz-Molina Noemi Vidal Gerard Plans Carles Majós Judit Ribas María Antonia Baltrons Jose R. Bayascas Carlos Barcia Jordi Bruna Victor J. Yuste |
| author_sort | Laura Martínez-Escardó |
| collection | DOAJ |
| description | Glioblastoma (GBM) is a highly aggressive brain tumor and almost all patients die because of relapses. GBM-derived cells undergo cell death without nuclear fragmentation upon treatment with different apoptotic agents. Nuclear dismantling determines the point-of-no-return in the apoptotic process. DFF40/CAD is the main endonuclease implicated in apoptotic nuclear disassembly. To be properly activated, DFF40/CAD should reside in the cytosol. However, the endonuclease is poorly expressed in the cytosol and remains cumulated in the nucleus of GBM cells. Here, by employing commercial and non-commercial patient-derived GBM cells, we demonstrate that the natural terpenoid aldehyde gossypol prompts DFF40/CAD-dependent nuclear fragmentation. A comparative analysis between gossypol- and staurosporine-treated cells evidenced that levels of neither caspase activation nor DNA damage were correlated with the ability of each compound to induce nuclear fragmentation. Deconvoluted confocal images revealed that DFF40/CAD was almost completely excluded from the nucleus early after the staurosporine challenge. However, gossypol-treated cells maintained DFF40/CAD in the nucleus for longer times, shaping a ribbon-like structure piercing the nuclear fragments and building a network of bridged masses of compacted chromatin. Therefore, GBM cells can fragment their nuclei if treated with the adequate insult, making the cell death process irreversible. |
| first_indexed | 2024-03-10T06:04:35Z |
| format | Article |
| id | doaj.art-6413408650f8453789322c010a859186 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T06:04:35Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6413408650f8453789322c010a8591862023-11-22T20:37:20ZengMDPI AGCancers2072-66942021-11-011321557910.3390/cancers13215579Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma CellsLaura Martínez-Escardó0Montse Alemany1María Sánchez-Osuna2Alejandro Sánchez-Chardi3Meritxell Roig-Martínez4Salvio Suárez-García5Daniel Ruiz-Molina6Noemi Vidal7Gerard Plans8Carles Majós9Judit Ribas10María Antonia Baltrons11Jose R. Bayascas12Carlos Barcia13Jordi Bruna14Victor J. Yuste15Cell Death, Senescence and Survival Group, Departament de Bioquímica i Biologia Molecular and Institut de Neurociències, Facultat de Medicina, Campus de Bellaterra, Universitat Autònoma de Barcelona, 08193 Bellaterra, SpainCell Death, Senescence and Survival Group, Departament de Bioquímica i Biologia Molecular and Institut de Neurociències, Facultat de Medicina, Campus de Bellaterra, Universitat Autònoma de Barcelona, 08193 Bellaterra, SpainCell Death, Senescence and Survival Group, Departament de Bioquímica i Biologia Molecular and Institut de Neurociències, Facultat de Medicina, Campus de Bellaterra, Universitat Autònoma de Barcelona, 08193 Bellaterra, SpainServei de Microscopia, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, SpainNeuroimmunity Research Group, Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, SpainCatalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and BIST, 08193 Bellaterra, SpainCatalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and BIST, 08193 Bellaterra, SpainNeuro-Oncology Unit, Hospital Universitari de Bellvitge-ICO L’Hospitalet (IDIBELL), 089098 Barcelona, SpainNeuro-Oncology Unit, Hospital Universitari de Bellvitge-ICO L’Hospitalet (IDIBELL), 089098 Barcelona, SpainNeuro-Oncology Unit, Hospital Universitari de Bellvitge-ICO L’Hospitalet (IDIBELL), 089098 Barcelona, SpainPharmacology of Cellular Stress Group, Pharmacology Unit, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida/IRBLleida, 25198 Lleida, SpainCell Death, Senescence and Survival Group, Departament de Bioquímica i Biologia Molecular and Institut de Neurociències, Facultat de Medicina, Campus de Bellaterra, Universitat Autònoma de Barcelona, 08193 Bellaterra, SpainSignalling in the Central Nervous System Group, Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, SpainNeuroimmunity Research Group, Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, SpainNeuro-Oncology Unit, Hospital Universitari de Bellvitge-ICO L’Hospitalet (IDIBELL), 089098 Barcelona, SpainCell Death, Senescence and Survival Group, Departament de Bioquímica i Biologia Molecular and Institut de Neurociències, Facultat de Medicina, Campus de Bellaterra, Universitat Autònoma de Barcelona, 08193 Bellaterra, SpainGlioblastoma (GBM) is a highly aggressive brain tumor and almost all patients die because of relapses. GBM-derived cells undergo cell death without nuclear fragmentation upon treatment with different apoptotic agents. Nuclear dismantling determines the point-of-no-return in the apoptotic process. DFF40/CAD is the main endonuclease implicated in apoptotic nuclear disassembly. To be properly activated, DFF40/CAD should reside in the cytosol. However, the endonuclease is poorly expressed in the cytosol and remains cumulated in the nucleus of GBM cells. Here, by employing commercial and non-commercial patient-derived GBM cells, we demonstrate that the natural terpenoid aldehyde gossypol prompts DFF40/CAD-dependent nuclear fragmentation. A comparative analysis between gossypol- and staurosporine-treated cells evidenced that levels of neither caspase activation nor DNA damage were correlated with the ability of each compound to induce nuclear fragmentation. Deconvoluted confocal images revealed that DFF40/CAD was almost completely excluded from the nucleus early after the staurosporine challenge. However, gossypol-treated cells maintained DFF40/CAD in the nucleus for longer times, shaping a ribbon-like structure piercing the nuclear fragments and building a network of bridged masses of compacted chromatin. Therefore, GBM cells can fragment their nuclei if treated with the adequate insult, making the cell death process irreversible.https://www.mdpi.com/2072-6694/13/21/5579apoptosiscaspase-activated DNase (DFF40/CAD)glioblastoma (GBM)gossypolnuclear fragmentation/disassembly |
| spellingShingle | Laura Martínez-Escardó Montse Alemany María Sánchez-Osuna Alejandro Sánchez-Chardi Meritxell Roig-Martínez Salvio Suárez-García Daniel Ruiz-Molina Noemi Vidal Gerard Plans Carles Majós Judit Ribas María Antonia Baltrons Jose R. Bayascas Carlos Barcia Jordi Bruna Victor J. Yuste Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells Cancers apoptosis caspase-activated DNase (DFF40/CAD) glioblastoma (GBM) gossypol nuclear fragmentation/disassembly |
| title | Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells |
| title_full | Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells |
| title_fullStr | Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells |
| title_full_unstemmed | Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells |
| title_short | Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells |
| title_sort | gossypol treatment restores insufficient apoptotic function of dff40 cad in human glioblastoma cells |
| topic | apoptosis caspase-activated DNase (DFF40/CAD) glioblastoma (GBM) gossypol nuclear fragmentation/disassembly |
| url | https://www.mdpi.com/2072-6694/13/21/5579 |
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